The pressure of Big Pharma

A Globe and Mail analysis found financial conflicts of interest are commonplace in clinical practice guidelines. As 10 major Canadian pharmaceutical players prepare to release their total payments to physicians, some prominent doctors are dismissing the limited disclosure as meaningless

When the Anxiety Disorders Association of Canada set out to craft the official guidelines for managing anxiety, post-traumatic stress and obsessive-compulsive disorders, the non-profit organization recruited six top psychiatrists to lead the effort.

Those psychiatrists, in turn, approached their contacts in the pharmaceutical industry with a request: Will your company help pay for the development of our guidelines?

Nine drug makers, including the companies that make the antidepressants Prozac, Zoloft and Paxil, put up a total of $205,000, most of which went to cover flights, meals and Toronto hotel rooms for a meeting of the executive committee and to pay the salaries of two medical writers who helped research and draft the final guideline paper.

Of the 22 panelists who ultimately signed off on the paper – it was published in 2014 and is still among the 10 most-frequently accessed on the Canadian Medical Association’s database of 1,200 or so clinical practice guidelines – 13 disclosed that they had received payments from the pharmaceutical industry in the past, one of them from 16 different companies.

John Walker, the president of Anxiety Canada – as the association is now called – said the drug companies who sponsored the guideline paper had no say whatsoever in its advice. But the Winnipeg psychologist, one of the nine panelists who declared no financial ties to industry, acknowledged that the Big Pharma entanglements do not look good.

This chart show the relationship between panelists and pharmaceutical companies in the creation of one guideline

1 of the 22 panelists involved in the creation of the guideline had ties to 17 different pharmaceutical companies or other organizations

The 36 pharmaceutical companies and other organizations from which the panelists received funding

Lundbeck

Eli Lilly

1

AstraZeneca

Pfizer

2

Janssen Ortho

Boehringer-Ingelheim

3

Servier

GSK

Shire

4

Valeant

Bristol-Myers Squibb

5

Organon

Sunovion

6

Wyeth

Purdue Pharma

7

Biovail

Merck

8

Takeda

9

Labopharm

Novartis

10

Optum Health

Cephalon

11

Otsuka

12

Hamilton Academic

Health Sciences

Organization

13

14

15

Physicians

Postgraduate Press

Pierre Fabre

16 -

22

Clinique et

Developpement in

Virtuo Inc.

Roche

CME Outfitters

Litebook Company

Solvay

St. Jude's Medical

13CME

Forest Laboratories

Mochida

Genuine Health

None

Of the nine panelists who declared no financial conflicts, seven are psychologists, mental-health professionals who can’t prescribe medications.

THE GLOBE AND MAIL, SOURCE: Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders (published 2014)

This chart show the relationship between panelists and pharmaceutical companies in the creation of one guideline

1 of the 22 panelists involved in the creation of the guideline had ties to 17 different pharmaceutical companies or other organizations

The 36 pharmaceutical companies and other organizations from which the panelists received funding

Lundbeck

Eli Lilly

1

AstraZeneca

Pfizer

2

Janssen Ortho

Boehringer-Ingelheim

3

Servier

GSK

Shire

4

Valeant

Bristol-Myers Squibb

5

Organon

Sunovion

6

Wyeth

Purdue Pharma

7

Biovail

Merck

8

Takeda

9

Labopharm

Novartis

10

Optum Health

Cephalon

11

Otsuka

12

Hamilton Academic

Health Sciences

Organization

13

14

15

Physicians

Postgraduate Press

Pierre Fabre

16 -

22

Clinique et

Developpement in

Virtuo Inc.

Roche

CME Outfitters

Litebook Company

Solvay

St. Jude's Medical

13CME

Forest Laboratories

Mochida

Genuine Health

Of the nine panelists who declared no financial conflicts, seven are psychologists, mental-health professionals who can’t prescribe medications.

None

THE GLOBE AND MAIL, SOURCE: Canadian clinical practice guidelines for the management of

“With all that funding from industry,” he said, “I think it’s something that is reasonable for people to be concerned about for sure.”

Anxiety Canada’s 2014 paper is one of nine clinical practice guidelines, involving 212 panelists, that The Globe and Mail analyzed in the wake of a controversy over new recommendations for prescribing opioids, the powerful painkillers at the root of an epidemic of abuse and overdose deaths in Canada.

Federal Health Minister Jane Philpott ordered an external review of the opioid guidelines last month when it emerged that a third of those involved in crafting the advice had received payments from opioid makers, including one doctor who voted on the final recommendations despite the group’s promise to remain free of industry connections – a pledge that was in itself unusual.

The Globe’s analysis found that financial conflicts of interest are commonplace on guideline committees. Forty-six per cent of the panelists involved in the nine guideline documents reviewed by The Globe received some funding from companies that might benefit from a positive mention of their drugs. In three cases, more than 75 per cent of the panelists declared a conflict. In two, the guidelines were financed directly by the pharmaceutical industry.

Guideline panels play a particularly influential role in the practice of medicine. Front-line doctors usually don’t have the time to evaluate hundreds of studies before deciding which treatments are best for their patients. They rely on guideline panels to synthesize the information for them. Clinical practice guidelines have been used in medical malpractice cases to determine whether doctors accused of harming their patients have deviated from the standards of care for their field.

Official clinical practice guidelines can also have a dramatic impact on how drugs are prescribed. A seemingly minor change in the blood pressure or cholesterol levels at which medication is recommended could, for instance, result in millions more people taking anti-hypertensives or statins.

In Canada, there are no nationwide rules for how conflicts of interest should be divulged or what counts as a genuine conflict, leaving guideline committees who want to protect the integrity of their recommendations to set their own standards.

The true reach of pharmaceutical dollars into the guidelines examined by The Globe could be deeper than it appears because some of the committees only required doctors to disclose if they had received more than $5,000 or $10,000 from the industry. And in the one case in which no conflicts were declared – a guideline on the diagnosis and treatment of dementia aimed at family doctors – only the five main authors were asked to divulge their conflicts at the bottom of the document – even though more than 30 physicians took part in the conference that led to the recommendations.

The Globe’s analysis illuminates the pervasiveness of industry ties to Canada’s medical community, especially among the top-flight researchers and “key opinion leaders” who often sit on important guideline panels.

However, in Canada, these specific industry payments to doctors are shrouded in secrecy – unlike in the United States, where the Physician Payments Sunshine Act compels companies to divulge all payments of $10 or more to doctors. The U.S. legislation has generated a rich trove of data, allowing researchers to learn that gifts as small as a free meal can influence physicians’ prescribing behaviour.

“People will always deny that they’re influenced by conflicts that they may have. Those denials are often quite sincere,” said Joel Lexchin, a Toronto emergency physician and the author of a recent book on the cozy relationship between Big Pharma and Canadian doctors.

“I’m not accusing doctors of being bribed. But they may still be influenced – and that will influence the kind of recommendations that they make.”

On Tuesday, the Canadian branches of 10 major pharmaceutical players are expected to reveal the total amount they paid in 2016 to doctors and health-care organizations in this country, but some prominent physicians behind the new “Open Pharma” campaign for greater transparency are already dismissing the release of aggregate figures as a meaningless gesture.

Those doctors – including Dr. Lexchin – are urging the federal and provincial governments to step in and force drug companies to reveal their specific payments to physicians.

That’s a call the Canadian Medical Association, which represents doctors across the country, already supports.

When it comes to guideline panels, Jeff Blackmer, the CMA’s vice-president for medical professionalism, said it would be “ideal” for conflicted doctors to be prohibited from voting on final recommendations, although he conceded that could be difficult given Big Pharma’s pervasive influence.

“You may have someone who’s a real leading expert, who’s been sponsored for a couple of very important studies, and you have to decide: Do you disqualify that person?” Dr. Blackmer said. “It’s not a black-and-white issue. Ideally, you would have a completely clean sheet with no one who has ever taken a penny from industry. In reality, that can be difficult.”

In its analysis, The Globe tried to pick guidelines published in the past five years for a wide variety of medical conditions: hypertension, acne, attention-deficit hyperactivity disorder in children, anxiety and related disorders, dementia, two types of cancer, rheumatoid arthritis and chronic hepatitis C.

Funding of medical guidelines by the

pharmaceutical industry

CHRONIC Hepatitis C

An update on the management of chronic hepatitis C: 2015

consensus guidelines from the Canadian Association for the

Study of the Liver

panelists who received funding from

the pharmaceutical industry*

100%

ACNE Management

Management of Acne: Canadian clinical practice guideline.

(published 2015)

91%

RHEUMATOID ARTHRITIS

Management

Canadian Rheumatology Association Recommendations for

Pharmacological Management of Rheumatoid Arthritis with

Traditional and Biologic Disease-modifying Antirheumatic

Drugs. (published 2012)

75%

ANXIETY MANAGEMENT

Canadian clinical practice guidelines for the management of

anxiety, posttraumatic stress and obsessive-compulsive

disorders (published 2014)

59%

HYPERTENSION

Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk

Assessment, Prevention and Treatment of Hypertension in

Adults

51%

Prostate CANCER

Bone Health and Bone-targeted therapies for prostate cancer,

Cancer Care Ontario. (published 2016)

32%

YOUTH ADHD

Canadian Guidelines on Pharmacotherapy for Disruptive and

Aggressive Behaviour in Children and Adolescents with

Attention-Deficit Hyperactivity Disorder, Oppositional Defiant

Disorder, or Conduct Disorder (published 2015)

25%

Colon CANCER

Adjuvant systemic chemotherapy for Stage II and III colon

cancer following complete resection, Cancer Care Ontario

(published 2015)

22%

DEMENTIA TREATMENT

Fourth Canadian Consensus Conference on the Diagnosis and

Treatment of Dementia, recommendations for family

physicians (published 2014)

0%

*In some cases, panelists who declared a conflict of interest

were prohibited from voting on the final recommendations.

THE GLOBE AND MAIL, SOURCE: The Canadian Medical

Association’s Infobase

Funding of medical guidelines by the

pharmaceutical industry

CHRONIC Hepatitis C

An update on the management of chronic hepatitis C: 2015 consensus

guidelines from the Canadian Association for the Study of the Liver

panelists who received funding from

the pharmaceutical industry*

100%

ACNE Management

Management of Acne: Canadian clinical practice guideline. (published

2015)

91%

RHEUMATOID ARTHRITIS

Management

Canadian Rheumatology Association Recommendations for

Pharmacological Management of Rheumatoid Arthritis with Traditional

and Biologic Disease-modifying Antirheumatic Drugs. (published 2012)

75%

ANXIETY MANAGEMENT

Canadian clinical practice guidelines for the management of anxiety,

posttraumatic stress and obsessive-compulsive disorders (published

2014)

59%

HYPERTENSION

Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment,

Prevention and Treatment of Hypertension in Adults

51%

Prostate CANCER

Bone Health and Bone-targeted therapies for prostate cancer,

Cancer Care Ontario. (published 2016)

32%

YOUTH ADHD

Canadian Guidelines on Pharmacotherapy for Disruptive and Aggressive

Behaviour in Children and Adolescents with Attention-Deficit

Hyperactivity Disorder, Oppositional Defiant Disorder, or Conduct

Disorder (published 2015)

25%

Colon CANCER

Adjuvant systemic chemotherapy for Stage II and III colon cancer

following complete resection, Cancer Care Ontario (published 2015)

22%

DEMENTIA TREATMENT

Fourth Canadian Consensus Conference on the Diagnosis and Treatment

of Dementia, recommendations for family physicians (published 2014)

0%

*In some cases, panelists who declared a conflict of interest

were prohibited from voting on the final recommendations.

THE GLOBE AND MAIL, SOURCE: The Canadian Medical

Association’s Infobase

Funding of medical guidelines by the pharmaceutical industry

CHRONIC Hepatitis C

An update on the management of

chronic hepatitis C: 2015 consensus

guidelines from the Canadian

Association for the Study of the Liver

panelists who received

funding from

the pharmaceutical

industry*

100%

ACNE Management

Management of Acne: Canadian clinical

practice guideline. (published 2015)

91%

RHEUMATOID ARTHRITIS

Management

75%

Canadian Rheumatology Association

Recommendations for Pharmacological

Management of Rheumatoid Arthritis with

Traditional and Biologic Disease-modifying

Antirheumatic Drugs. (published 2012)

ANXIETY MANAGEMENT

Canadian clinical practice guidelines for the

management of anxiety, posttraumatic stress

and obsessive-compulsive disorders

(published 2014)

59%

HYPERTENSION

Hypertension Canada’s 2017 Guidelines for

Diagnosis, Risk Assessment, Prevention and

Treatment of Hypertension in Adults

51%

Prostate CANCER

Bone Health and Bone-targeted therapies for

prostate cancer, Cancer Care Ontario.

(published 2016)

32%

YOUTH ADHD

Canadian Guidelines on Pharmacotherapy for

Disruptive and Aggressive Behaviour in

Children and Adolescents with

Attention-Deficit Hyperactivity Disorder,

Oppositional Defiant Disorder, or Conduct

Disorder (published 2015)

25%

Colon CANCER

Adjuvant systemic chemotherapy for

Stage II and III colon cancer following

complete resection, Cancer Care Ontario

(published 2015)

22%

DEMENTIA TREATMENT

Fourth Canadian Consensus Conference on

the Diagnosis and Treatment of Dementia,

recommendations for family physicians

(published 2014)

0%

*In some cases, panelists who declared a conflict of interest were prohibited from voting on the final

recommendations.

THE GLOBE AND MAIL, SOURCE: The Canadian Medical Association’s Infobase

The Globe interviewed representatives from all the committees by phone or e-mail, but it did not contact all the individual panelists.

In the case of the Canadian Association for the Study of the Liver (CASL,) a professional organization of liver-disease researchers and doctors, all five of the authors of its 2015 update on the management of chronic hepatitis C disclosed receiving money from drug companies, including the makers of direct-acting antivirals, a new generation of drugs that can cure the liver-damaging virus in about three months but can cost tens of thousands of dollars per patient. (The real prices of the drugs are secret, but they are believed to have come down considerably after the federal-provincial-territorial alliance that negotiates confidential drug prices on behalf of public drug plans reached a deal on the new drugs in February.)

The guideline authors, all of whom are considered top experts in their field, received their payments for consulting, giving speeches or conducting research, according to the disclosures made at the bottom of their guideline paper.

Gilead Sciences Canada, Merck Canada and Bristol-Myers Squibb Canada – the three makers of direct-acting antivirals who inked the February pricing deal – provided payments of one kind or another to every member of the panel, with one minor exception. (Merck provided payments to only four of the five doctors.)

As CASL president Rick Schreiber pointed out, the hepatitis C guidelines were not funded by the industry, nor is CASL itself. The group also recently set up a guideline committee that will act at arm’s length from the association and will evaluate potential conflicts of interest before deciding who should be allowed to sit on future guideline panels.

“We’re trying to take as many steps as possible to ensure the highest ethical standards for guidelines,” said Dr. Schreiber, a professor of pediatrics at the University of British Columbia and the director of the B.C. pediatric liver-transplant program. “We think we have ethical standards [already,] but we’re putting all these things in.”

The Canadian Rheumatology Association is another group whose guideline developers are awash in financial conflicts of interest, although the guideline itself was funded by a Canadian Institutes of Health Research grant, not the industry.

Twelve of the 16 panelists who crafted the association’s 2012 recommendations for the pharmacological management of rheumatoid arthritis disclosed that they had received more than $10,000 in “ honoraria” from the pharmaceutical industry in the three years before the document was published.

Of the four members who declared they were conflict-free, two were patient advocates, one was a family doctor and another was a researcher. The rest were rheumatologists – specialists in a field that has undergone a sea change in the past two decades thanks to the rise of a pricey new class of biologic medicines called disease-modifying antirheumatic drugs, or DMARDs, which can put the autoimmune disorder into remission.

The two most expensive and widely used drugs in the category, Remicade and Humira, cost on average $27,300 and $15,800 a year, respectively, according to the federal body that regulates drug prices in Canada. Sales of DMARDs, which are also used to treat other conditions, almost doubled between 2010 and 2015. They now account for more than 10 per cent of all public drug-plan spending in the country.

The Canadian Rheumatology Association said by e-mail that it is taking a fresh look at its conflict-of-interest policy. “Excluding people based on very strict criteria may exclude many experts, and impact the quality of the guideline. This is traditionally why we’ve chosen disclosure of [conflicts of interest] rather than exclusion. However, we are currently reviewing our [conflict-of-interest] policies.”

Many of the guideline representatives who spoke to The Globe expressed concern that automatically excluding all the physicians who have received money from the pharmaceutical industry would leave guideline committees without critical expertise, particularly in niche specialties.

“Within a small group like this, it’s very difficult to find dermatologists in Canada who have not had some dealings with industry,” said Jerry Tan, a Windsor dermatologist and the co-chair of a panel that produced the Canadian clinical practice guideline on the management of acne.

Dr. Tan was one of the 10 doctors on the panel who divulged receiving payments from the pharmaceutical industry. Only one of the panelists had not. The acne guideline was directly funded with about $120,000 from five drug companies, according to Dr. Tan, who himself has worked as an adviser, consultant or clinical investigator for nine different companies, according to the disclosure published at the bottom of the guideline.

However, he said that he and his co-chair were “very conscious of the risk of bias and of how conflict of interest might be construed” as they led the guideline process. They solicited funds from between 15 and 20 companies, then kept the identity of the five funders secret from the rest of the panel and recused themselves from all voting.

Several other guideline committees have also tried to erect safeguards that would allow conflicted doctors to share their knowledge without unduly influencing the final recommendations.

In the case of Hypertension Canada, for example, just over half of the 80 doctors involved in the 2017 guidelines for managing high blood pressure declared a conflict of some sort with industry.

But the non-profit organization keeps Big Pharma’s influence in check by barring all panelists from voting on sections of the guideline in which their potential conflicts of interest might come into play. It also has a central review committee comprised of methodological experts with no industry affiliations.

Cancer Care Ontario, a government agency that produced two of the guidelines reviewed by The Globe, does not allow conflicted physicians to chair its guideline panels. It also leaves the final word on its recommendations to an approval panel with no conflicts.

For Daniel Gorman, a psychiatrist at the Hospital for Sick Children in Toronto who helped to craft the Canadian guidelines related to attention-deficit hyperactivity disorder in children, the influence of the pharmaceutical industry remains a “big problem.” He was one of nine members of the panel who received no payments from industry. Three others declared conflicts.

He is skeptical of his counterparts who say Big Pharma’s financial influence can be difficult to escape.

“Is it hard to avoid getting into relationships where they’re actually paying you to do research or give talks?” Dr. Gorman said. “That’s not difficult. You just say no.”

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